The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the present invention.
The present patent application relates to treatment and prevention of acute injuries, and prevention or reversal of states of chronic mitochondrial depletion or dysfunction.
Mitochondria are specialized compartments present in cells that are responsible for creating more than 90% of the energy needed by the body to sustain life and support growth. When mitochondrial function fails, less energy is generated within the cell. Cell injury and ultimately cell death follow. A number of drug classes have recently been identified as inducing organ degeneration or other side effects which are mediated by their effects on mitochondrial bioenergetics. The most frequent targets in drug-induced mitochondrial dysfunction are the heart, liver and kidneys, although other organs can also be affected. A recent summary by Pereira et al. in Current Drug Safety, 4: 34-54, 2009 (hereby incorporated by reference in its entirety) includes the following non-limiting list of exemplary drugs and drug classes:
1. Cardiovascular Toxicity
    Nucleoside reverse transcriptase inhibitors (NRTIs); Zidovudine (AZT); Bupivacaine; Lidocaine; Thiazolidinediones (TZD); Doxorubicin (DOX); Sorafenib; Daunorubicin; Epirubicin; Idarubicin; Celecoxib; Diclofenac; Ibuprofen; Indomethacin; Mefenamic acid; Meloxicam; Naproxen; Piroxicam; Sulindac; Atenolol; Pioglitazone; Rosiglitazone2. Hepatic Toxicity    Isoniazid; Valproic acid; Tamoxifen; Flutamide; Lamivudine; Zidovudine (AZT); Zalcitabine; Phenoformin; Metformin; Nefazodone; Abacavir; Didanosine; Nevirapine; Tenofovir; Stavudine; Ketoconazole; Divalproex Sodium3. Renal Toxicity    Doxorubicin (DOX); Cysplatin; Gentamicin; Cyclosporin A; Ifosfamide; Statins; Tenofovir
This understanding is also discussed in detail in Gohil et al., Nature Biotechnol. 28: 249-257, 2010; and Wagner et al., and Nature Biotechnol. 26: 343-351, 2008, each of which is hereby incorporated by reference in its entirety. Reflecting this understanding, the phrase “mitochondrial toxicity” as used herein refers to failure of the mitochondria resulting from the administration of chemical compositions to a subject. The manifestations of mitochondrial toxicity can be quite varied, due to the different functions carried out by the mitochondria. These functions include:                Oxidative phosphorylation, in which substrates are oxidized by the enzymes of the mitochondrial respiratory chain in order to establish an electrochemical gradient of protons across the mitochondrial membrane. This potential is used by ATP synthase to produce ATP, the energy currency of the body;        Citric acid cycle, the reactions of which occur inside the mitochondrial matrix and which lead to the production to NADH and succinate under aerobic conditions; and        Calcium homeostasis and the permeability transition pore. Calcium concentrations inside the mitochondrial matrix depend not only of an electrogenic mitochondrial calcium uniporter (MCU) but also on antiporters (Na+/Ca2+ and H+/Ca2+). Inside mitochondria, calcium modulates the activity of several important enzymes. An excess of calcium accumulation in the matrix leads to the formation of the mitochondrial permeability transition pore, which spans the inner and outer mitochondrial membrane and whose opening leads to the collapse of the transmembrane electric potential, ultimately leading to mitochondrial and cellular dysfunction.        
Given these varied functions, it is perhaps not surprising that mitochondria can be affected by chemical exposure at various levels. These include uncoupling of oxidative phosphorylation, inhibition of key enzymes, inhibition of fatty acid metabolism, effecting permeability pores, inducement of apoptosis, inhibition of mitochondrial protein synthesis, and/or reduction in total mitochondrial numbers.
There remains a need in the art for prophylactic and therapeutic approaches for the treatment of mitochondrial toxicity.